PROJECT SUMMARY/ABSTRACT Very little is known about the potential role of the gut microbiome in the enduring and prevalent conse- quences of chemotherapy on the brain and behavior (e.g., cognitive impairments). The long-term goal for this work is to determine how to manipulate the mechanisms underlying debilitating behavioral sequelae due to cancer treatments for preventative or therapeutic results. This R01 project is our response to NCI Provocative Question #10: How do microbiota affect the response to cancer therapies? The overall objective of this work is to determine the role of gut microbiome-brain interactions in chemotherapy-related cognitive problems. The central hypothesis for this project is that chemotherapy shifts diversity in the gut microbiota, which leads to neuroinflammation and cognitive impairments. Thus, the rationale for this work is that understanding how can- cer treatment alters brain function via the gut microbiome will elucidate novel, more effective, and non-invasive targets of intervention to improve quality of life in this rapidly-growing population. Four specific aims are pro- posed to test the central hypothesis using both a non-metastatic mouse model of breast cancer and breast cancer patients. Aim 1 is to determine the role of chemotherapy-induced changes in the gut microbiome on behavior. Using our mouse cancer model, we will study the relationship between learning and memory behav- ior and gut microbial sequence diversity with chemotherapy treatment. Aim 2 will identify the necessi- ty/sufficiency of changes in the gut microbiome on chemotherapy-induced behaviors. Our approach for this aim is to directly manipulate the gut microbiome in this mouse model through either the use of microbe-free mice or probiotic treatment. Aim 3 is designed to identify the role of the gut microbiome in chemotherapy-induced neu- ral alterations relevant to cognition. Using brain tissue from the prior gut manipulations, cellular and molecular neurobiological approaches will be taken to pinpoint the effects of the gut microbiome on brain pathways that regulate cognition in the context of cancer/chemotherapy. Finally, Aim 4 is an exploratory clinical aim for the translation of this work into a chemotherapy-treated breast cancer population. Here, we will determine the clini- cal longitudinal relationship between the consequences of chemotherapy on the gut microbiome and behavior- al comorbidities. The contribution of this work will be significant because it will launch the discussion of har- nessing gut-brain interactions for the treatment and understanding of behavioral comorbidities common to can- cer and other chronic diseases. The proposed research is innovative because it is an evolved and substantial departure from the existing approaches to the chemobrain problem based on new transformative research on gut-brain communication. Our team and environment at Ohio State University is uniquely positioned to carry out this combined translational and clinical approach for this high-priority and innovative research endeavor. The PI is a New and Early Investigator.